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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Several studies have demonstrated that protein–protein interactions control the expression of HDACs through: (a) alternative RNA splicing; (b) the modulation of the availability of cofactors; (c) varied subcellular localization; and (d) different degrees of proteolytic processing (Gallinari et al., 2007; Seto and Yoshida, 2014). Individual HDAC proteins, especially HDAC1 and HDAC2, are generally low in enzyme activity; however, when associated with protein complexes such as Sin3, nucleosome remodeling and deacetylase (NuRD), and co-repressor for element-1-silencing transcription factor (CoREST), they exhibit enhanced function, indicating the importance of protein–protein interactions in controlling their biological activity (Banks et al., 2018).
Proinflammatory Peptides in Sensory Nerves of the Airways
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Peter Baluk, Donald M. McDonald
Immunohistochemistry using antibodies to receptors has allowed a more precise cellular localization of NK-1 receptors (Fig. 4). In rat trachea, abundant NK-1 receptor immunoreactivity is present on endothelial cells of postcapillary venules that are the sites of tachykinin-induced plasma leakage (92) (Fig. 4B) and on epithelial cells and submucosal glands (122) (Fig. 4C). However, there is no detectable staining of arterioles, even though these vessels are directly innervated by substance P-containing nerves. This approach also permits the subcellular localization of receptors and visualization of the intracellular trafficking of receptors. When NK-1 receptors are stimulated by substance P, they are internalized into endosomes together with their ligand (Figs. 4A–4C). The internalization is blocked by the NK-1 receptor antagonist SR 140333 (92). The number of endosomes gives a quantitative index of receptor number and activation, and this number parallels the degree of leakage observed in different vessels (Fig. 5). As a consequence the pool of cell surface receptors is reduced, and the cell is desensitized to further stimulation (92,270). Thus, the process of receptor internalization, together with associated phosphorylation of stimulated receptors (271), contributes to tachyphylaxis. Eventually the internalized receptors are recycled to the cell surface, and the cells are resensitized to substance P (92,272).
Familial Hyperparathyroidism
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Luigia Cinque, Alfredo Scillitani, Vito Guarnieri
The CDC73 gene encodes for a ubiquitously expressed protein, namely parafibromin, whose role is described below. Inactivating mutations are scattered throughout the coding sequence with particular high frequencies for the exon 1, 2, and 7 [61], that could be considered such mutational hot-spots. Mutations can be missense, nonsense, frameshift, or affecting the splicing sites [61]. In the vast majority, whether translated, mutated proteins are instable and thus degraded by through a proteasome mediated process [62,63], indicating that the loss of expression typical of tumor suppressor genes is the base of the tumorigenesis CDC73-induced. In a few cases a different mutational effect, affecting the subcellular localization, has been reported: instead the mutation alters the nucleolar localization signal (NoLS), making it impossible for the protein to reach the right subcellular compartment [62,63]. More recently, large genomic deletions at the CDC73 locus (1q31.2) were also identified [41,64,65,67–72]. The deletions may involve single or multiple exons or even encompass the whole genomic region along with flanking genes. In these latter cases, additional neurodevelopmental symptoms were recorded [71] that could be ascribed to the other genes deleted.
Proteomics-inspired precision medicine for treating and understanding multiple myeloma
Published in Expert Review of Precision Medicine and Drug Development, 2020
Matthew Ho, Giada Bianchi, Kenneth C. Anderson
While cytogenetic studies have undoubtedly advanced our understanding of MM, they are limited by the comparatively small number of genetic abnormalities that can be measured as prior knowledge of the abnormality is needed for probe (FISH) or assay (aCGH) design. Furthermore, epigenetic changes and functional gene expression are not captured by these methodologies. Gene expression profiling (GEP) is therefore a powerful tool that can be used to define clinically relevant subsets of MM. A study utilizing GEP found 20 phenotypically distinct types of MM that differ in their clinical behavior and response to treatment [84]. Ultimately, however, it is properly folded proteins (and not genes) that perform crucial functions across all biological processes. Because mRNA still has to undergo a number of regulatory steps (RNA metabolism → ribosomal protein synthesis → post-translational modifications → protein clearance) before a functional protein is produced, changes in gene expression may not truly be reflected at the level of the proteome [85]. Moreover, GEP is unable to provide information on the subcellular localization of proteins or protein-protein interactions; both of which are crucial to protein function [86]. It is therefore intuitive that protein analysis is an ideal approach, when feasible, to accurately portray changes in protein expression, post-translational modifications, and protein-protein interactions characterizing MM pathogenesis.
Cell penetrating peptides: the potent multi-cargo intracellular carriers
Published in Expert Opinion on Drug Delivery, 2019
Kimia Kardani, Alireza Milani, Samaneh H. Shabani, Azam Bolhassani
An ideal DDS should specifically penetrate into the target cells, and accumulate in the specific tissue [122]. CPPs are effective tools for drug delivery into cells, but they do not have specificity to cell type [126]. Most CPPs were nonspecifically linked to membranes of all cell types due to overall expression of heparin sulfate proteoglycan [149]. Recent efforts were performed using the activatable CPPs (ACPPs), the stimuli-responsive CPPs, and the specific localization sequences to deliver toward the proper cellular organelles [148]. There are different subcellular localization sequences with distinct properties that target a cytosolic protein to a specific organelle such as the endoplasmic reticulum (ER), nucleus, mitochondria, and chloroplast [230]. Recent use of CPPs was focused on development of NLS, pH/temperature-sensitive targeted delivery, and synergistic effects of targeting ligands and CPPs [97]. In fact, some nanoparticle delivery systems were designed to activate CPPs, and drug release under specific conditions such as hyperthermy (40–42◦C), low pH (< 6), light (UV), and interaction with specific enzymes (matrix metalloproteinases, thrombin, and legumain) in tumor tissue [5]. Among amino acids used in CPPs, histidine is an essential amino acid with a protonable imidazolyl group which is needed for many enzymatic activities. For example, the replacement of tryptophan (W) by histidine (H) in the antimicrobial peptide sequence R2W2RW2R2 increased the antibacterial activity [240].
Isolation and characterization of mesenchymal stem cells and its antitumor application on ovarian cancer cell line
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Farideh Mohammadian, Babak Negahdari
Protein associations offer a mechanistic basis for most biological processes in an organism. A human molecular interaction network of genes connected to the MeSH keyword “Mesenchymal stem cell” was acquired from Gene2MeSH. Genes molecular interactions were acquired from Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) Web site [17]. Originally STRING was employed as a search tool for repeated instances of neighbouring genes, the v10 of STRING has become a database for understanding protein–protein interaction containing validated and predicted protein–protein target information. The web service and database success is driven by the vast amount of information contained in the database and the intuitive method in its running analyses. The entering of one or several protein identifiers permits a better comprehension of protein–protein interactions and developing significant information on a level of network. Using predicted proteins which had crosstalk with Oct-4 (POU5F1) and NANOG as entries, CellWhere server [18] were used for gene association networks graphical display organized on a subcellular localizations. With a query list of proteins or genes, CellWhere gives an interactive graphical demonstration that mimics cell structure, displaying the local network interaction organized into a subcellular location. This user-friendly server aids in the mechanistic hypotheses design by enabling the experimental biologist to concurrently discover two elements of functional context: (i) protein subcellular localization and (ii) gene functional or protein–protein interactions.